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Restoration of Natural Killer Cell Antimetastatic Activity by IL12 and Checkpoint Blockade
Isabel Ohs1, Laura Ducimetière1, Joana Marinho1
1Inflammation research, Institute of Experimental Immunology, University of Zurich, Switzerland.
Abstract:
Immune checkpoint therapies target tumor antigen-specific T cells, but less is known about their effects on natural killer (NK) cells, which help control metastasis. In studying the development of lung metastases, we found that NK cells lose their cytotoxic capacity and acquire a molecular signature defined by the expression of coinhibitory receptors. In an effort to overcome this suppressive mechanism, we evaluated NK cell responses to the immunostimulatory cytokine IL12. Exposure to IL12 rescued the cytotoxicity of NK cells but also led to the emergence of an immature NK cell population that expressed high levels of the coinhibitory molecules PD-1, Lag-3, and TIGIT, thereby limiting NK cell-mediated control of pulmonary metastases. Notably, checkpoint blockade therapy synergized with IL12 to fully enable tumor control by NK cells, demonstrating that checkpoint blockers are not only applicable to enhance T cell-mediated immunotherapy, but also to restore the tumor-suppressive capacity of NK cells. Cancer Res; 77(24); 7059-71. ©2017 AACR.
Insights
Immune checkpoint therapy can enhance natural killer (NK) cell function against cancer metastasis. Combining checkpoint blockade with IL12 restores NK cell cytotoxicity and tumor control.
Area of Science:
- Immunology
- Cancer Biology
- Cellular Therapeutics
Background:
- Immune checkpoint inhibitors primarily target T cells, with less known about their impact on natural killer (NK) cells in controlling metastasis.
- NK cells are crucial for anti-metastasis immunity but can lose function and express coinhibitory receptors within the tumor microenvironment.
Purpose of the Study:
- To investigate the effects of IL12 on NK cell function and their role in controlling lung metastasis.
- To evaluate the potential of combining IL12 with immune checkpoint blockade to enhance NK cell-mediated anti-tumor immunity.
Main Methods:
- Studied the development of lung metastases in preclinical models.
- Analyzed NK cell cytotoxic capacity and molecular signatures, including coinhibitory receptor expression (PD-1, Lag-3, TIGIT).
- Assessed NK cell responses to IL12 and combined IL12 with checkpoint blockade therapy.
Main Results:
- NK cells in metastatic lung tumors exhibited reduced cytotoxicity and expressed coinhibitory receptors.
- IL12 treatment restored NK cell cytotoxicity but induced an immature NK cell population expressing PD-1, Lag-3, and TIGIT, limiting metastasis control.
- Combination therapy of checkpoint blockade and IL12 synergistically enhanced NK cell activity and achieved complete tumor control.
Conclusions:
- Immune checkpoint blockade can restore the tumor-suppressive capacity of NK cells.
- The combination of IL12 and checkpoint blockade represents a promising strategy to enhance NK cell-mediated immunotherapy for cancer treatment.
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